Myeloid neoplasm driver mutations (JAK2, KIT, BCR-ABL, FLT3)
Core concept
- Almost all are constitutively activated tyrosine kinases signalling through JAK-STAT / RAS-MAPK / PI3K without ligand
| Mutation | Disease | Drug |
|---|---|---|
| BCR::ABL1 t(9;22) | CML (and Ph+ ALL) | Imatinib, nilotinib, dasatinib, ponatinib for T315I, asciminib (allosteric, myristoyl pocket) |
| JAK2 V617F (exon 14) | PV ~95%, ET ~55-60%, MF ~55-65% | Ruxolitinib, fedratinib |
| JAK2 exon 12 | PV only, ~3% (the JAK2 V617F-negative PV) | |
| CALR (exon 9) | ET ~25%, MF ~25% - better prognosis, higher platelets, lower thrombosis than JAK2 | |
| MPL W515 | ET/MF ~5% | |
| KIT D816V | Systemic mastocytosis (>90%) - not an MPN | Avapritinib, midostaurin; imatinib-RESISTANT |
| FIP1L1::PDGFRA (del4q12) | Chronic eosinophilic leukaemia / myeloid neoplasm with eosinophilia | Exquisitely imatinib-sensitive at low dose |
| FLT3-ITD / TKD | AML ~25-30% | Midostaurin (with induction), gilteritinib (relapsed/refractory), quizartinib |
| NPM1 | AML ~30% of normal-karyotype | Menin inhibitors (revumenib, ziftomenib) |
| IDH1/IDH2 | AML ~15-20% | Ivosidenib, enasidenib |
- KIT D816V is the classic distractor - a myeloid driver, but of mastocytosis, and the D816V substitution blocks imatinib binding
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